Avastin(Bevacizumab)+Nexavar(sorafenib)

[Olga]

Bonnie - I answer to you here to keep it classified.
It is very good news that Ashley is stable on this combo and that her primary is showing such a high % of necrosis. ASPS is a highly vascular tumour and angiogenesis inhibitors may have an application in their treatment.
As far as I know there is only one person from our community who was on a Avastin in a clinical trial setting - Adam - with a short lived response and then he developed a resistance - may be his family member can add their comments later.
Generally Bevacizumab (Avastin), Sunitinib (Sutent) and Sorafenib (Nexavar) are anti-cancer drugs targeted to VEGF signaling pathway and all approved for other indications so they can be used off label.

This combination Avastin(generic name is Bevacizumab ) and Nexavar(generic name is sorafenib) is under a study now:
at the Vanderbilt-Ingram Cancer Center for Patients With Advanced Kidney Cancer and at the Maryland (Warren Grant Magnuson Clinical Center ) for Patients With Refractory, Metastatic, or Unresectable Solid Tumors. But these two studies are Phase 1-2 so there are no results yet. I hope that your oncologist can at least contact them to check for the side effects their people are having - is the regiment that Ashley is getting the same like they have?
the link to the NCI trial is http://www.clinicaltrials.gov/ct/show/N ... 92?order=3
Good luck and thank you for keeping us posted!

[bonniecharron]

In the post for the vaccine trial a couple people have talked about the anti-angiogenic drug treatment at Dana Farber, what are the drugs that are being used.
We are currently back on the Nexavar and Avastin after a long summer of complications, did not have anything to do with the two drugs, porta cath had to be removed and new one put in, took a long time to heal.
We did see improvement in the lungs while on the two drugs, and when Ashley was off for almost 2 months we saw growth in the lung mets.
Hopefully the 2 drugs start to work again.

[Yosef Landesman]

Dear Bonni,
Can you please summarize the total benefit from the use of Nexavar and Avastin: What was the net effect on the size/growth rate of the primary tumor and the lung mets? What is the dose of the two anti-angiogenic drugs and how often is the treatment. Will you please answer in the folder “Anti Angiogenic treatments”. Regarding your question, I will soon update on the status of the GVAX clinical trial and the proposed Anti-angiogenic treatment for ASPS at the Dana Farber.
Best Wishes,
Yossi

[bonniecharron]

Ashley had a PET/CT scan last week. Results we were told were stable to slight improvement. Primary tumor is showing less activity again on this scan.
In her lungs some mets have decreased in size and some mets have increased in size, the overall metastatic burden to lungs is not significantly changed. This is good because while she was off the meds for over a month we had some growth in the lungs.
This is the toughest chemo Ashley has been on, she has some loss of appetite and is having a tough time keeping weight on. She has lost her hair also, this is a first for her since she started treatment almost 4 years ago.
She continues to attend college full time and still has a positive attitude that we will win this battle. We will continue on this path with nexavar and avastin.
We have been staying in contact with the individual who has done her molecular studies and he is always checking on any new drugs that come out.

[Olga]

Bonnie - it is sad to hear that Ashley has lost her hair, but I hope that it will worth it. Is it done on a clinical trial - I have posted the link before - or on the compassionate basis?

[Fictional]

Hello, we're very new to this, but we would appreciate any other information you can give us about the anti-angiogenesis factors. Our 10 year old daughter has a pelvic tumor and she is undergoing bone scan and finer resolution chest CT next week to decide the next step.

One thing we are considering is treatment with Avastin for a brief course, then resection of the primary tumor. The surgeon said the smaller the tumor, the better as far as he is concerned. Our dilemma is whether to seek a wide resection (which could involve nearly all her pelvic contents on that side, with colostomy and bladder divert) or try Avastin 1-2 months, then conservative resection.

We wanted to inform ourselves (and her) as much as possible about what side effects she could get into.

Many thanks for all of you who are sharing your time and information so generously.

'F'

[Olga]

'F', our community experience with Avastin is very limited, we only had two people on it. It's side effects are not severe although there are cases of the spontaneous bleeding but it usually happens in older people or bulky tumors. The real danger of the Avastin is that it can cause the regression of the tumor in one location but later progression in the other location as when it restricts the growth of the new blood vessels it doesn't affect the old ones which can even improve, get wider and stronger in absence of the competition and no space limitation.
There is some info reg. its side effects on the PubMed.gov if you do a search by "Bevacizumab" - it is a generic name of the Avastin.

[Yosef Landesman]

Dear 'F',

One of our ASPS members was treated with Avastin for 4 months in 2004. Based on his relative reports, the Avastin was very effective for the first 30 days. The first CT scan at the end of the first month showed dramatic shrinkage in existing lung mets. The 2nd scan after two months of treatment showed no change, and the scan after the third month also showed no change - no new mets, no new growth, but also no shrinkage of existing mets. The reported side effect were sore joints. Four months after the beginning of the Avastin treatment tumor growth was seen again and the treatment was stopped.

[Fictional]

Our latest is leaning toward SUTENT, but Dana Farber's Tumor Board meets on Tuesday.

I am curious about the discussion re: molecular analysis suggesting SUTENT would not be beneficial. Based on the reference to Geisinger Labs, I am wondering if the tissue typing refers to their proteomic analysis (immunohistochemical staining) of the tumor.

Avastin and SUTENT have similar but not identical profiles, and at least to my knowledge, they are not simply distinguishable on the basis of tumor staining of the type done by Geisinger.

There is a tremendous interest in molecularly typing the tumors in order to find out in advance who is likely or unlike to respond to particular regimen. One of our friends put us into contact with one of the initial investigators who developed SUTENT and she suggested the possibility of having our daughters tumor sent for kinase analysis - a more technically difficult testing than immunostaining, but potentially one that can yield more specific information. I am wondering if this is the project that the iCURE is funding with John Goldberg?

Another question I had was relevant to the TFE3 genotype. Our daughter has this translocation, but based on my reading, some people develop more complex genetic profiles the longer they have the cancer - and this also contributes to the complexity of their response. It would be nice to know if any of the molecular details we can find out about our kids can help decide the best next step in therapy.

Because ASPS is so rare, it is difficult to consider numbers or percentages in terms of response. There are too few people and other potential variables that we won't know about. But since some common molecular mechanisms have been found with other tumors (c-met), we are thinking that looking in the responses of these tumors can yield some helpful information.

In our situation, we may have a local tumor (thought potentially incompletely resectable) or early metastasis situation. A short course of SUTENT is being used in an attempt to shrink the tumor and hopefully make a more complete resection without removal of vital structures. We aren't really looking for a complete response with SUTENT alone. This may be the difference in our current clinical situation. In other studies of molecularly similar tumors, we found that SUTENT seemed to have a more dramatic tumor shrinkage response (as I recall about 40% SUTENT, 2% Avastin), but more tumors (80%) in this series (renal CA) seemed like they responded to Avastin in some way (e.g. stable growth).

I don't know whether all this scientific detail is helpful to this forum, and I am not an expert in this area. I just want to share our lines of investigation for any who are interested. Both my husband and I did basic research in molecular mechanisms of cancers and we are physicians.

[Yosef Landesman]

We have no idea if either Nexavar (Sorafenib) or Sutent (Sunitinib) are effective in treating ASPS. In this “Forum” you read that we know one case of response when Nexavar was given in combination with Avastin.
You are right, both Nexavar (Sorafenib) and Sutent (Sunitinib) are pretty similar in their mode of action. They inhibit target members of two classes of kinases known to be involved in both cell proliferation (growth) and angiogenesis (blood supply). While saying that it should be emphasized that the originality of Nexavar is that it is also targeting the Raf kinase and therefore may inhibit also the Ras pathway.
Nexavar targets are: Raf kinase (of the Ras pathway). VEGFR-1, VEGFR-2, VEGFR-3, PDGFR-B, KIT, FLT-3 and RET.
Sutent targets are: VEGF-R, PDGF-R, KIT, FLT-3, RET and CSF-1R.
It is a good idea to perform ASPS tumor profiling from as many as possible patients. I agree that a significant finding from kinase profiling has potentially a lot of value as it may indicate which type of therapies could be used to treat a patient. For example, finding that the RAS pathway is active in ASPS may potentially indicate that Nexavar is preferred over Sutent for ASPS patients. Yes, this is one of the projects which are supported by iCureASPS, a study which is done at the Dana Farber. Geisinger Labs have indications on RAS activation in ASPS, but to my knowledge this was not confirmed yet in samples from other patients.

Regarding your question on the TFE3 genotype: One of two types of TFE3 translocations are found in ASPS: (type 1 and type 2, see the information on our website). The translocation may be one of the earliest events that lead to the formation of ASPS and all the ASPS tumor cells contain the translocation. Since the nature of cancer is that tumors are genetically unstable, late stage ASPS tumor cells contain additional genetic modifications which make the cancer more aggressive and harder to treat.